Resolution With racemisation

Resolution of compounds made as diastereoisomeric mixtures The synthesis of Jacobsen s Mn(III) epoxidation catalyst by resolution Resolution with half an equivalent of resolving agent Physical Separation of Enantiomers Chromatography on chiral columns Resolution of triazole fungicides by HPLC A commercial drug separation by chiral HPLC Differential Crystallisation or Entrainment of Racemates Conglomerates and racemic compounds Typical procedure for differential crystallisation (entrainment) Conventional resolution ofL-methyl DOPA Resolution ofL-methyl DOPA by differential crystallisation Finding a differential crystallisation approach to fenfluramine Resolution with Racemisation... 

Resolution of amino acids by differential crystallisation with racemisation Differential crystallisation and racemisation when enolisation is impossible Kinetic resolution with racemisation... 

Other methods of racemisation during resolution the Mannich reaction Resolution with racemisation in the manufacture of a drug Resolution with Enzymes... 

Kinetic resolution with racemisation using proteolytic enzymes... 

Resolution with racemisation is used in the manufacture of the cardioprotective drug CP-060.S 111 by the Chugai Pharmaceutical company.27 The drug itself can be resolved with some difficulty but as it is made from the simpler carboxylic acid 112 this looks a better bet. 

Pseudomonas is found in the section below on Dynamic Kinetic Resolutions. We will meet Pseudomonas fluorescens again in the next chapter where we also see enzymes in kinetic resolutions with racemisation of starting material (dynamic kinetic resolution). 

In Chapter 22 we saw resolution with racemisation applied to the synthesis of L-364,718. That could have been described as a dynamic resolution or possibly even a dynamic thermodynamic resolution but not a dynamic kinetic resolution as it did not depend on one enantiomer reacting faster than the other. Rather it depended on the thermodynamic stability of one crystalline form over the other. 

Kinetic resolution with racemisation Enzymes versus whole organisms Desymmetrisation with lipases Immobilised enzymes in desymmetrisation Polymer-supported reagents and enzymes Effects of amines on lipases and esterases Other acylating enzymes Enzymatic Oxidation... 

For the enantiopure production of human rhinovirus protease inhibitors scientists from Pfizer developed a kinetic resolution and recycling sequence (Scheme 6.14 A). The undesired enantiomer of the ester is hydrolysed and can be racemised under mild conditions with DBU. This enzymatic kinetic resolution plus racemisation replaced a significantly more expensive chemical approach [52]. An enzymatic kinetic resolution, in combination with an efficient chemically catalysed racemisation, is the basis for a chiral building block for the synthesis of Talsaclidine and Revatropate, neuromodulators acting on cholinergic muscarinic receptors (Scheme 6.14B). In this case a protease was the key to success [53]. Recently a kinetic resolution based on a Burkholderia cepacia lipase-catalysed reaction leading to the fungicide Mefenoxam was described [54]. Immobilisation of the enzyme ensured >20 cycles of use without loss of activity (Scheme 6.14 C). 

The enzymes of the nucleic acid metabolism are used for several industrial processes. Related to the nucleobase metabolism is the breakdown of hydantoins. The application of these enzymes on a large scale has recently been reviewed [85]. The first step in the breakdown of hydantoins is the hydrolysis of the imide bond. Most of the hydantoinases that catalyse this step are D-selective and they accept many non-natural substrates [78, 86]. The removal of the carbamoyl group can also be catalysed by an enzyme a carbamoylase. The D-selective carbamoylases show wide substrate specificity [85] and their stereoselectivity helps improving the overall enantioselectivity of the process [34, 78, 85]. Genetic modifications have made them industrially applicable [87]. Fortunately hydantoins racemise readily at pH >8 and additionally several racemases are known that can catalyze this process [85, 88]. This means that the hydrolysis of hydantoins is always a dynamic kinetic resolution with yields of up to 100% (Scheme 6.25). Since most hydantoinases are D-selective the industrial application has so far concentrated on D-amino acids. Since 1995 Kaneka Corporation has produced 2000 tons/year of D-p-hydroxyphenylglycine with a D-hydantoinase, a d-carbamoylase [87] and a base-catalysed racemisation [85, 89]. 

Resolution of amino acids by differential crystallisation with racemisation... 

Even more complicated reactions can be used to racemise during a resolution. The amino ketone 102 is needed for the synthesis of the analgesic and useful asymmetric reagent (see chapter 24) DARVON. Classical resolution with dibenzoyl tartaric acid 9 succeeds in crystallising the (+) enantiomer and racemising the mother liquors by reverse Mannich reaction.25... 

Remarkable is DSM s process for the preparation of (D)-phenylglycine by classical resolution with in situ racemisation. The imine of phenylglycinamide, prepared in a Strecker reaction, is readily racemised, so that in the presence of (R)-mandelic acid, the (D)-phenylglycinamide crystallises out almost quantitatively. In acidic medium, the mandehc acid is separated off and recycled the remaining amide is cleaved to yield free (D)-phenylglycine. 

It is a combination of these twin goals that has led to the evolution of classical kinetic resolution into DKR. In such a process, one can in principle obtain a quantitative yield of one of the enantiomers. Effectively, DKR combines the resolution step of kinetic resolution with an in situ equilibration or racemisation of the chirally labile substrate. In DKR, the enantiomers of a... 

The ability of enzymes to achieve the selective esterification of one enantiomer of an alcohol over the other has been exploited by coupling this process with the in situ metal-catalysed racemisation of the unreactive enantiomer. Marr and co-workers have used the rhodium and iridium NHC complexes 44 and 45 to racemise the unreacted enantiomer of substrate 7 [17]. In combination with a lipase enzyme (Novozyme 435), excellent enantioselectivities were obtained in the acetylation of alcohol 7 to give the ester product 43 (Scheme 11.11). A related dynamic kinetic resolution has been reported by Corberdn and Peris [18]. hi their chemistry, the aldehyde 46 is readily racemised and the iridium NHC catalyst 35 catalyses the reversible reduction of aldehyde 46 to give an alcohol which is acylated by an enzyme to give the ester 47 in reasonable enantiomeric excess. 

You and co-workers have demonstrated a further application of NHCs in the kinetic resolution of formyl p-lactams ( )-265 [103]. Upon treatment with a chiral NHC, the Breslow-type intermediate is formed, followed by ring-opening of the P-lactam moiety, with subsequent trapping of the acylazolium intermediate leading to the enantio-enriched succinimide product 266 and resolved formyl P-lactam (which is reduced to its alcohol 267). The authors note that when R" = H, the products undergo racemisation readily, and this is a possible explanation for the lower levels of enantioselectivity observed in the succinimide products 266 (Scheme 12.60). 

This method is closely related with the one just described. In both the cases the racemate is converted into a pair of diastereomers, the only difference is that resolution via diastereomers involves the formation of stable chemical compounds, while resolution via molecular complexes gives readily decomposable molecular compounds only. The latter method is advantageous in that the preparation and decomposition of molecular compounds take place under mild conditions which reduce the possibility of racemisation to a minimum. 

Isooctane Racemic resolution of several Naproxen analogues combined with the re-racemisation of the second enantiomer [132, 133]... 

Figure 2.6 By resolution of df-amino acid esters under conditions of dynamic resolution 100% of a single enantiomer may be produced. Using catalytic amounts of pyiidoxyl-5-phosphate, which forms a Schiff s base with the ester and not the acid, the unreacted D-ester may be racemised in situ and for instance L-tyrosin has been obtained in 97% ee and 95% yield.

Fortuitously simultaneous selective reaction and racemisation reactions can be achieved by using two different microorganisms with lactamase and lactam racemase activities respectively, since both have the same pH optimum (pH 8-9). Thus quantitative yields of L-lysine are obtained, rather than the 50% yields usual in resolution processes. In... 

An elegant way to avoid the low yields and the need for recycling half of the material in the case of kinetic resolutions is a dynamic kinetic resolution (DKR). The dynamic stands for the dynamic equilibrium between the two enantiomers that are kinetically resolved (Scheme 6.6A). This fast racemisation ensures that the enzyme is constantly confronted with an (almost) racemic substrate. At the end of the reaction an enantiopure compound is obtained in 100% yield from racemic starting material. Mathematical models describing this type of reaction have been published and applied to improve this important reaction [32, 33]. There are several examples, in which the reaction was performed in water (see below). In most cases the reaction is performed in organic solvents and the hydrolase-catalysed reaction is the irreversible formation of an ester (for example see Figs. 9.3, 9.4, 9.6, 9.12) or amide (for example see Figs. 9.13, 9.14, 9.16). 

When looking at the above described dynamic kinetic resolution from a green point of view, then one thing can immediately be noticed This reaction would be unnecessary if the starting material had been synthesized enantioselectively. A much more efficient way of performing a dynamic kinetic resolution is thus to start with a prochiral material. The reversible addition of another building block to this prochiral starting material is not only the formation of a new bond but at the same time a pathway for the rapid racemisation of the intermediate... 

A straightforward approach to avoid low yields is to perform the reaction as a dynamic kinetic resolution. Racemisation can be achieved chemically [33] or enzymatically, indeed a number of N-acyl amino acid racemases have been described and it has been demonstrated that they could be employed together with the l-N-acyl amino acylase for the production of optically pure methionine [81]. 

DSM developed a slightly different approach towards enantiopure amino acids. Instead of performing the Strecker synthesis with a complete hydrolysis of the nitrile to the acid it is stopped at the amide stage. Then a stereoselective amino acid amidase from Pseudomonas putida is employed for the enantioselective second hydrolysis step [83], yielding enantiopure amino acids [34, 77, 78]. Although the reaction is a kinetic resolution and thus the yields are never higher than 50% this approach is overall more efficient. No acylation step is necessary and the atom efficiency is thus much higher. A drawback is that the racemisation has to be performed via the Schiff s base of the D-amide (Scheme 6.23). 

Recently it was reported that an a-amino-e-caprolactam racemase from Achro-mobacter obae can racemise a-amino acid amides efficiently. In combination with a D-amino acid amidase from Ochrobactrum anthropi L-alanine amide could be converted into D-alanine. This tour de force demonstrates the power of the racemase [84]. If racemic amide is used as a starting material the application of this racemase in combination with a d- or L-amidase allows the preparation of 100% d- or L-amino acid, a dynamic kinetic resolution instead of DSM s kinetic resolution (Scheme 6.24). 

With the object, therefore, of definitely establishing the configuration of tropine and of pseudo-tropine, we have conducted experiments on the resolution of these bases, and some of their derivatives, by fractionally crystallising their salts with certain optically active acids. It may at once be stated that the results of these experiments point to the conclusion that both the bases in question are internally compensated compounds. The relation between them must, therefore, be of the nature of a cis-trans-isomerism, as concluded by Willstatter. (loc. cit.). Attempts were made to racemise tropine by heating the latter at high temperatures with hydrochloric acid, but these were unsuccessful. Source Barrowcliff 1909... 

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